1. Field of the Invention
The present invention relates to a series of substituted pyridone compounds. More specifically, the present invention relates to a series of 2,3,5-substituted pyridone derivatives. This invention also relates to methods of making these compounds. The compounds of this invention are inhibitors of poly(adenosine 5′-diphosphate ribose) polymerase (PARP) and are, therefore, useful as pharmaceutical agents, especially in the treatment and/or prevention of a variety of diseases including diseases associated with the central nervous system and cardiovascular disorders.
2. Description of the Prior Art
Poly(adenosine 5′-diphosphate ribose) polymerase [poly(ADP-ribose) polymerase, PARP, EC 2.4.2.30] also known as poly(ADP-ribose) synthetase (PARS) is a chromatin-bound nuclear enzyme of eukaryotic cells, present at about 2×105 molecules/nucleus. The high degree of evolutionary conservation of PARP in multicellular organisms can be taken as an indication of the physiological importance of poly(ADP-ribosyl)ation. Activated by DNA strand breaks, PARP transfers ADP-ribose units from NAD+ to nuclear proteins including histones and PARP itself. This reaction generates poly(ADP) ribose and nicotinamide, with the latter being a negative feedback inhibitor of PARP. The role of NAD+ in this sequence is distinct from its role as a redox cofactor in other enzymatic processes. The poly(ADP-ribose) thus formed typically contains on the order of 200 ribose units having linear and branched connections with one branch approximately every 25 units of ADP-ribose. The links are by α-(1″-2′)ribosyl-glycosic bonds. Because of the negative charges on the ADP-ribose polymers, poly(ADP-ribosylated)proteins lose their affinity for DNA and are, therefore, inactivated. Poly(ADP-ribosyl)ation is an immediate, covalent, but transient post-translational modification. Poly(ADP-ribose) is in a dynamic state, its rapid synthesis being followed by degradation that is catalyzed by the enzyme poly(ADP) glycohydrolase (PARG). Thus, PARP and other modified proteins are returned to their native state. For reviews on PARP see: Liadet. L., “Poly(adenosine 5′-diphosphate) ribose polymerase activation as a cause of metabolic dysfunction in critical illness”; Current Opinions Clin. Nutrition Metabolic Care, 5, 175-184 (2002). Burkle, A., “Physiology and pathophysiology of poly(ADP-ribosyl)ation”; BioEssays, 23, 795-806 (2001). Hageman, G. J. and Stierum, R. H., “Niacin, Poly(ADP-ribose) polymerse-1 and genomic stability”; Mutation Res., 475, 45-56 (2001). Smith, S., “The world according to PARP”; Trends Biochem Sci., 26, 174-179 (2001). Tong, W.-M. et al., Poly(ADP-ribose) polymerase: a guardian angel protecting the genome and suppressing tumorigenisis”; Biochim. Biophys. Acta, 1552, 27-37 (2001).
In cerebral ischemia, calcium influx into neurons causes the activation of nitric oxide synthase, leading to production of nitric oxide and subsequently the reactive radical peroxynitrite. Peroxynitrite causes extensive damage to DNA and results in uncontrolled activation of PARP. Cellular NAD and ATP are quickly used up and the cell dies a necrotic death due to loss of the source of cellular energy. DNA is similarly damaged by peroxynitrite in myocardial ischemia and in inflammation.
Several studies with PARP −/− animals and with a variety of inhibitors support the role of PARP in the pathophysiology of a number of disease models. In a stroke model, for example, the infarct size in PARP-deficient animals is 80% smaller compared to control PARP +/+ animals. See, for example, Eliasson, M. J. L. et al., “Poly(ADP-ribose)polymerase gene disruption renders mice resistant to cerebral ischemia”; Nature Med., 3, 1089 (1997). In addition, many studies using various PARP inhibitors (e.g. 3-aminobenzamide, GPI 6150, PJ-34 and nicotinamide) have shown reduction in stroke-induced infarction volume and reduced behavioral deficits in post-stroke treatment paradigms. See, generally, Takahashi, K. et al., “Post-treatment with an inhibitor of poly(ADP-ribose) polymerase attenuates cerebral damage in focal ischemia”; Brain Res., 829, 46, (1999). Mokudai, T. et al., “Delayed treatment with nicotinamide (vitamin B3) improves neurological outcome and reduces infarct volume after transient focal ischemia in Wistar rats”; Stroke, 31, 1679 (2000). Abdelkarim, G. E. et al., “Protective effects of PJ34, a novel, potent inhibitor of poly(ADP ribose) polymerase (PARP) in vitro and in vivo models of stroke”; Int. J. Mol. Med., 7, 255 (2000). Ding, Y. et al., “Long-term neuroprotective effect of inhibiting poly(ADP-ribose) polymerase in rats with middle cerebral artery occlusion using a behavioral assessment”; Brain Res., 915, 210 (2001).
Other disease models in which the role of PARP has been established by using inhibitors or the knockout are streptozocin-induced diabetes (see, Mabley, J. G. et al., “Inhibition of poly(ADP-ribose) synthetase by gene disruption or inhibition with 5-iodo-6-amino-1,2-benzopyrone protects mice from multiple-low-dose-streptozotocin-induced diabetes”; Br. J. Pharmacol., 133, 909-919 (2001); Gale, E. A. et al., “Molecular mechanisms of beta-cell destruction in IDDM: the role of nicotinamide”; Horm. Res., 45, 39-43 (1996); and Heller, B. et al., “Inactivation of the poly(ADP-ribose) polymerase gene affects oxygen radical and nitric oxide toxicity in islet cells”; J. Biol. Chem., 270, 11176-11180 (1995).
PARP is also implicated in diabetic cardiomyopathy, see, Pacher, P. et al., “The role of poly(ADP-ribose) polymerase activation in the development of myocardial and endothelial dysfunction in diabetes”; Diabetes, 51, 514-521 (2002); and in head trauma, see, LaPlaca, M. C. et al., “Pharmacological inhibition of poly(ADP-ribose) polymerase is neuroprotective following traumatic brain injury in rats”; J. Neurotrauma, 18, 369-376 (2001). Also see, Verma, A., “Opportunities for neuroprotection in traumatic brain injury”; J. Head Trauma Rehabil., 15, 1149-1161 (2000).
Further diseases involving PARP include myocardial ischemia, see generally, Pieper, A. A. et al., “Myocardial postischemic injury is reduced by poly(ADP-ribose) polymerase-1 gene disruption”; Mol. Med., 6, 271-282 (2000). Also see, Grupp, I. L. et al., “Protection against hypoxia reoxygenation in the absence of poly(ADP-ribose) synthetase in isolated working hearts”; J. Mol. Cell. Cardio., 31, 297-303 (1999).
Additional diseases include experimental allergic encephalomyelitis (EAE), see for example, Scott, G. S. et al., “Role of poly(ADP-ribose) synthetase activation in the development of experimental allergic encephalomyelitis”; J. Neuroimmunology, 117, 78-86 (2001).
It has also been reported that cancer may be effectively treated with a PARP inhibitor combined with a chemotherapeutic agent or radiation therapy, see for example, Martin, N. M., “DNA repair inhibition and cancer therapy”; J. Photochem. Photobiol. B, 63, 162-170 (2001). Finally, aging related diseases also have been implicated due to PARP, see Von Zglinicki, T. et al., “Stress, DNA damage and aging—an integrative approach”; Exp. Geront., 36, 1049-1062 (2001). Also see, Rosenthal, D. S. et al., “Poly(ADP-ribose) polymerase and aging”; in “The role of DNA damage and repair in aging”, Gilchrist, B. A. and Bohr, V. A., eds., Elsevier Science B. V. (2001), pp 113-133.
It is known from literature (see for example Cristina Cosi, Expert Opin. Ther. Patents, 2002, 12, 1047-1071; Southan et al., Current Medicinal Chemistry, 2003, 10, 321-340) that a few different classes of chemical compounds can be employed as PARP-inhibitors, such as derivatives of indoles, benzimidazoles, isoquinolinones or quinazolinones. It is of interest to note that most of the known PARP-inhibitors are derivatives of a bi- or polycyclic backbone.
Pyridone derivatives are known to have a potential for being used as pharmaceuticals, but none of these derivatives so far have been reported to feature any activity on the PARP enzyme. Even more importantly, the pyridone derivatives described in the literature differ significantly from those of the present invention.
For example, U.S. Pat. No. 4,699,914 discloses pyridone derivatives, which can be employed for the treatment of congestive heart failure in a patient. They differ from the compounds of the present invention in that the substitution at position 5 of the pyridone ring requires a phenylene or thienylene moiety, which in turn have to be substituted with imidazol-1-yl. In contrast, the substituent Ar of the pyridone derivatives of the present invention involve aryl, aryloyl or heteroaryl, including thienyl or phenyl. However, said aryl may not be substituted further with any other heteroaromatic residue. Instead, the pyridones of the present invention require a substitution of the Ar with a linker group Y.
U.S. Pat. No. 4,431,651 relates to 3,4-dihydro-5-(pyridinyl or phenyl)-2(1H)-pyridinones, which are used as cardiotonics. As disclosed in detail below, the pyridones of the present invention are structurally different from these compounds.
All of the references described herein are incorporated herein by reference in their entirety.
Since diseases such as myocardial infarction, which can be treated by the inhibition of PARP, are a very serious risk for the health of humans and other mammals, there is a significant demand for new pharmaceuticals having a beneficial therapeutic profile for the treatment of such diseases. Accordingly, there exists a strong need to provide further compounds having an inhibitory effect on PARP.
Therefore, it is an object of this invention to provide a series of substituted pyridone derivatives that are potent, selective inhibitors of PARP.
It is also an object of this invention to provide processes for the preparation of the substituted pyridone derivatives as disclosed herein.
Other objects and further scope of the applicability of the present invention will become apparent from the detailed description that follows.